Method for restoring a damaged or degenerated intervertebral disc

Abstract

The present invention relates to a minimally-invasive method for restoring a damaged or degenerated intervertebral disc at an early stage. The method comprises the step of administering an injectable in situ setting formulation in the nucleus pulposus of the damaged or degenerated disc of the patient. The formulation once injected combines with nucleus matters and host cells, and becomes viscous or gels in situ within the annulus fibrosus of the disc for increasing the thickness and volume of the damaged or degenerated disc. The formulation is retained within the disc for providing restoration of the damaged or degenerated disc.

1 . A method for restoring a damaged or degenerated intervertebral disc, said method comprising the step of:
 administering percutaneously an injectable in situ setting formulation in the nucleus pulposus of the damaged or degenerated disc of a patient for increasing the thickness of the damaged or degenerated disc, said formulation becoming viscous, or pasty or turning into a gel or solid in situ within the disc, is retained within the annulus fibrosus of the disc for providing restoration of the damaged or degenerated disc,   wherein said injectable in situ setting formulation comprises:   a) 0.1 to 5.0% by weight of a water soluble cellulose, polysaccharide or polypeptide, or a mixture thereof; and   b) i) 1.0 to 20% by weight of a salt of polyol or sugar selected from the group comprising mono-phosphate dibasic salt, mono-sulfate salt and a mono-carboxylic acid salt of polyol or sugar; or
 ii) 1.0 to 20% by weight of a salt selected from the group comprising phosphate, carbonate, sulfate and sulfonate. 
   wherein said solution has a pH ranging from 6.5 to 7.4, and turns into a gel within a temperature range from 20 to 70° C., said gel increasing the thickness of the disc, providing a mechanical support once injected in the disc.   
     
     
         2 . The method of  claim 1 , wherein said injectable in situ setting formulation once administered mixes and combines in situ nucleus matters and host cells present in the intervertebral disc. 
     
     
         3 . The method of  claim 1 , wherein said injectable in situ setting formulation comprises a thermogelling aqueous solution containing at least chitosan. 
     
     
         4 . The method of  claim 1 , wherein said injectable in situ setting formulation comprises a thermogelling aqueous solution containing at least one phosphate salt. 
     
     
         5 . The method of  claim 1 , wherein said injectable in situ setting formulation comprises a polymeric aqueous solution covalently crosslinkable into an aqueous gel in situ. 
     
     
         6 . The method of  claim 1 , wherein said injectable in situ setting formulation contains chondroitin sulfate, or hyaluronic acid, or poly(ethylene glycol). 
     
     
         7 . The method of  claim 1 , wherein said salt is a mono-phosphate dibasic salt of glycerol selected from the group consisting of glycerol-2-phosphate, sn-glycerol 3-phosphate and L-glycerol-3-phosphate salts. 
     
     
         8 . The method of  claim 1 , wherein said salt is a mono-phosphate dibasic salt and said polyol is selected from the group consisting of histidinol, acetol, diethylstilbestrol, indole-glycerol, sorbitol, ribitol, xylitol, arabinitol, erythritol, inositol, mannitol, and glucitol or a mixture thereof. 
     
     
         9 . The method of  claim 1 , wherein said salt is a mono-phosphate dibasic salt and said sugar is selected from the group consisting of fructose, galactose, ribose, glucose, xylose, rhamnulose, sorbose, erythrulose, deoxy-ribose, ketose, mannose, arabinose, fuculose, fructopyranose, ketoglucose, sedoheptulose, trehalose, tagatose, sucrose, allose, threose, xylulose, hexose, methylthio-ribose, and methylthio-deoxy-ribulose, or a mixture thereof. 
     
     
         10 . The method of  claim 1 , wherein said salt is a mono-phosphate dibasic salt and said polyol is selected from the group consisting of palmitoyl-glycerol, linoleoyl-glycerol, oleoyl-glycerol, and arachidonoyl-glycerol, or a mixture thereof. 
     
     
         11 . The method of  claim 1 , wherein said formulation comprises an aqueous solution selected from the group consisting of chitosan-β-glycerophosphate, chitosan-α-glycerophosphate, chitosan-glucose-1-glycero-phosphate, and chitosan-fructose-6-glycerophosphate. 
     
     
         12 . The method of  claim 1 , wherein said formulation comprises methyl-cellulose, hydroxyethyl cellulose, hydroxypropyl-methylcellulose, or a mixture thereof. 
     
     
         13 . The method of  claim 1 , wherein said injectable formulation comprises a water-soluble biopolymer selected from the group consisting of cellulose, polysaccharide, polypeptide, collagen, methylcellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose and a mixture thereof. 
     
     
         14 . The method of  claim 13 , wherein said biopolymer is polymerized or covalently crosslinked after being injected in situ. 
     
     
         15 . The method of  claim 1 , wherein said injectable formulation is a dispersion comprising a nonsoluble solid component. 
     
     
         16 . The method of  claim 17 , wherein said nonsoluble solid component comprises microparticles, microbeads, microspheres or granules. 
     
     
         17 . The method of  claim 1 , wherein said injectable in situ setting formulation is nonaqueous and comprises an organic solvent. 
     
     
         18 . The method of  claim 1 , wherein said injectable in situ setting formulation comprises at least one fatty acid, said fatty acid being selected from the group consisting of oleate, palmitate, myristate, stearate, palmitoleate, and vaccenate. 
     
     
         19 . The method of  claim 18 , wherein the fatty acid is mixed with a metabolically absorbable solvent or liquid vehicle to reduce viscosity and allow injectability. 
     
     
         20 . The method of  claim 1 , wherein said formulation contains at least one bioactive agent or drug. 
     
     
         21 . The method of  claim 20 , wherein said bioactive agent or drug is a cell stimulant. 
     
     
         22 . The method of  claim 21 , wherein the cell stimulant is selected from the group consisting of growth factors and cytokines. 
     
     
         23 . The method of  claim 1 , wherein the injectable formulation comprises living tissue cells prior to administration. 
     
     
         24 . The method of  claim 1 , wherein the injectable formulation comprises living tissue cells adhered onto a solid substrate. 
     
     
         25 . The method of  claim 1 , wherein the injectable formulation is flowable, but has a viscosity above 10 mPa·s at the time of administration. 
     
     
         26 . The method of  claim 1 , wherein the nucleus pulposus is excised prior to administering the formulation. 
     
     
         27 . The method of  claim 1 , wherein the restoration of the degenerated or damaged intervertebral disc provides a more biomechanically stable spine. 
     
     
         28 . A method for restoring a damaged or degenerated intervertebral disc, said method comprising the step of:
 administering percutaneously an injectable in situ setting formulation in the nucleus pulposus of the damaged or degenerated disc of a patient for increasing the thickness of the damaged or degenerated disc, said formulation becoming viscous, or pasty or turning into a gel or solid in situ within the disc, is retained within the annulus fibrosus of the disc for providing restoration of the damaged or degenerated disc,   wherein said injectable in situ setting formulation comprises:   a) 0.1 to 5.0% by weight of chitosan or collagen, or a mixture thereof; and   b) i) 1.0 to 20% by weight of a salt of polyol or sugar selected from the group consisting of mono-phosphate dibasic salt, mono-sulfate salt and a mono-carboxylic acid salt of polyol or sugar; or
 ii) 1.0 to 20% by weight of a salt selected from the group comprising phosphate, carbonate, sulfate and sulfonate; 
   wherein said solution has a pH ranging from 6.5 to 7.4, and turns into a gel within a temperature range from 20 to 70° C., said gel increasing the thickness of the disc, providing a mechanical support once injected in the disc.   
     
     
         29 . A method for restoring a damaged or degenerated intervertebral disc, said method comprising the step of:
 administering percutaneously an injectable in situ setting formulation in the nucleus pulposus of the damaged or degenerated disc of a patient for increasing the thickness of the damaged or degenerated disc, said formulation becoming viscous, or pasty or turning into a gel or solid in situ within the disc, is retained within the annulus fibrosus of the disc for providing restoration of the damaged or degenerated disc,   wherein said injectable in situ setting formulation comprises:   a) 0.1 to 5.0% by weight of chitosan or collagen, or a mixture thereof; and   b) i) 1.0 to 20% by weight of a salt of polyol or sugar selected from the group consisting of mono-phosphate dibasic salt, mono-sulfate salt and a mono-carboxylic acid salt of polyol or sugar; or
 ii) 1.0 to 20% by weight of a salt selected from the group comprising phosphate, carbonate, sulfate and sulfonate; and 
   c) 0.01 to 10% by weight of a water-soluble chemically reactive organic compound;   wherein said formulation has a pH ranging from 6.5 to 7.4, and turns into a gel within a temperature range from 4 to 70° C., said gel increasing the thickness of the disc, providing a mechanical support once injected in the disc.   
     
     
         30 . A nucleus pulposus formulation comprising at least one fatty acid, wherein said formulation forms a solid material in situ, said material allowing to increase the thickness of a damaged or degenerated disc, said solution being retained within the annulus fibrosus of the disc for providing restoration of the damaged or degenerated disc. 
     
     
         31 . A nucleus pulposus formulation comprising:
 a) 0.1 to 5.0% by weight of a water-soluble polymer selected from the group consisting of cellulosic, polysaccharide and polypeptidic, and   b) 1.0 to 20% by weight of a water-soluble salt selected from the group consisting of phosphate, glycerol-phosphate, glucose-phosphate, and fructose phosphate, or the like,   wherein said formulation has a pH ranging from 6.5 to 7.4, and turns into a gel within a temperature range from 20 to 70° C., said gel having a physiologically acceptable consistency for increasing the thickness of the disc, providing a mechanical support once injected in the disc.